Fibromodulin Explained

Fibromodulin is a protein that in humans is encoded by the FMOD gene.^{[1] [2]}

Fibromodulin is a 42kDa protein of a family of small interstitial leucine-rich repeat proteoglycans (SLRPs). It can have up to four N-linked keratan sulfate chains attached to the core protein within the leucine-rich region. It shares significant sequence homology with biglycan and decorin.^[3]

Function

Fibromodulin participates in the assembly of the collagen fibers of the extracellular matrix. It binds to the same site on the collagen type I molecule as lumican.^[4] It also inhibits fibrillogenesis of collagen type I and collagen type III in vitro.^{[5] [6]} It regulates TGF-beta activities by sequestering TGF-beta into the extracellular matrix.^[2]

Clinical significance

There is an age-dependent decline in the synthesis of keratan sulfate chains, so non-glycated forms of fibromodulin can accumulate in tissues such as cartilage.^[7]

Fibromodulin is found in the epidermis of human skin and is expressed by skin cells (keratinocytes) in culture. Mice with the gene for fibromodulin knocked out (Fmod-/-) have very fragile skin^[8] and abnormal tail and Achilles tendons.^[9] The collagen fiber bundles in these tendons are fewer and disorganised and there is less endotenon surrounding the tendon tissue. The levels of lumican, a SLRP with one of the same collagen binding sites as fibromodulin, is increased 4 fold in the tail tendons of Fmod-knockout mice.

Further reading

• Roughley PJ, Lee ER . Cartilage proteoglycans: structure and potential functions . Microscopy Research and Technique . 28 . 5 . 385–97 . Aug 1994 . 7919526 . 10.1002/jemt.1070280505 . 43194492 .
• Hildebrand A, Romarís M, Rasmussen LM, Heinegård D, Twardzik DR, Border WA, Ruoslahti E . Interaction of the small interstitial proteoglycans biglycan, decorin and fibromodulin with transforming growth factor beta . The Biochemical Journal . 302 . 2 . 527–34 . Sep 1994 . 8093006 . 1137259 . 10.1042/bj3020527.
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Research . 6 . 9 . 791–806 . Sep 1996 . 8889548 . 10.1101/gr.6.9.791 . free .
• Westergren-Thorsson G, Norman M, Björnsson S, Endrésen U, Stjernholm Y, Ekman G, Malmström A . Differential expressions of mRNA for proteoglycans, collagens and transforming growth factor-beta in the human cervix during pregnancy and involution . Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease . 1406 . 2 . 203–13 . Mar 1998 . 9573366 . 10.1016/S0925-4439(98)00005-2 . free .
• Font B, Eichenberger D, Goldschmidt D, Boutillon MM, Hulmes DJ . Structural requirements for fibromodulin binding to collagen and the control of type I collagen fibrillogenesis--critical roles for disulphide bonding and the C-terminal region . European Journal of Biochemistry . 254 . 3 . 580–7 . Jun 1998 . 9688269 . 10.1046/j.1432-1327.1998.2540580.x . free .
• Schaefer L, Gröne HJ, Raslik I, Robenek H, Ugorcakova J, Budny S, Schaefer RM, Kresse H . Small proteoglycans of normal adult human kidney: distinct expression patterns of decorin, biglycan, fibromodulin, and lumican . Kidney International . 58 . 4 . 1557–68 . Oct 2000 . 11012890 . 10.1046/j.1523-1755.2000.00317.x . free .
• Gori F, Schipani E, Demay MB . Fibromodulin is expressed by both chondrocytes and osteoblasts during fetal bone development . Journal of Cellular Biochemistry . 82 . 1 . 46–57 . 2001 . 11400162 . 10.1002/jcb.1115 . 41342892 .
• Mayr C, Bund D, Schlee M, Moosmann A, Kofler DM, Hallek M, Wendtner CM . Fibromodulin as a novel tumor-associated antigen (TAA) in chronic lymphocytic leukemia (CLL), which allows expansion of specific CD8+ autologous T lymphocytes . Blood . 105 . 4 . 1566–73 . Feb 2005 . 15471955 . 10.1182/blood-2004-04-1233 . free .
• Mikaelsson E, Danesh-Manesh AH, Lüppert A, Jeddi-Tehrani M, Rezvany MR, Sharifian RA, Safaie R, Roohi A, Osterborg A, Shokri F, Mellstedt H, Rabbani H . Fibromodulin, an extracellular matrix protein: characterization of its unique gene and protein expression in B-cell chronic lymphocytic leukemia and mantle cell lymphoma . Blood . 105 . 12 . 4828–35 . Jun 2005 . 15741214 . 10.1182/blood-2004-10-3941 . free .
• Sjöberg A, Onnerfjord P, Mörgelin M, Heinegård D, Blom AM . The extracellular matrix and inflammation: fibromodulin activates the classical pathway of complement by directly binding C1q . The Journal of Biological Chemistry . 280 . 37 . 32301–8 . Sep 2005 . 16046396 . 10.1074/jbc.M504828200 . free .
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . Oct 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .
• Sjöberg AP, Trouw LA, Clark SJ, Sjölander J, Heinegård D, Sim RB, Day AJ, Blom AM . The factor H variant associated with age-related macular degeneration (His-384) and the non-disease-associated form bind differentially to C-reactive protein, fibromodulin, DNA, and necrotic cells . The Journal of Biological Chemistry . 282 . 15 . 10894–900 . Apr 2007 . 17293598 . 10.1074/jbc.M610256200 . free .
• Kalamajski S, Oldberg A . Fibromodulin binds collagen type I via Glu-353 and Lys-355 in leucine-rich repeat 11 . The Journal of Biological Chemistry . 282 . 37 . 26740–5 . Sep 2007 . 17623650 . 10.1074/jbc.M704026200 . free .

Notes and References

1. Sztrolovics R, Chen XN, Grover J, Roughley PJ, Korenberg JR . Localization of the human fibromodulin gene (FMOD) to chromosome 1q32 and completion of the cDNA sequence . Genomics . 23 . 3 . 715–7 . Mar 1995 . 7851907 . 10.1006/geno.1994.1567 .
2. Web site: Entrez Gene: FMOD fibromodulin.
3. Antonsson P, Heinegård D, Oldberg A . Structure and deduced amino acid sequence of the human fibromodulin gene . Biochim Biophys Acta . 1174 . 2 . 204–6 . 1993 . 8357838 . 10.1016/0167-4781(93)90117-V.
4. Book: Halper J . Proteoglycans and Diseases of Soft Tissues . Progress in Heritable Soft Connective Tissue Diseases . 802 . 49–58 . 2014 . 24443020 . 10.1007/978-94-007-7893-1_4 . Advances in Experimental Medicine and Biology . 978-94-007-7892-4 .
5. Ezura Y, Chakravarti S, Oldberg A, Chervoneva I, Birk DE . Differential expression of lumican and fibromodulin regulate collagen fibrillogenesis in developing mouse tendons . J. Cell Biol. . 151 . 4 . 779–88 . 2000 . 11076963 . 10.1083/jcb.151.4.779 . 2169450.
6. Kalamajski S, Oldberg A . Fibromodulin binds collagen type I via Glu-353 and Lys-355 in leucine-rich repeat 11. . J Biol Chem . 282 . 37 . 26740–5 . 2007 . 17623650 . 10.1074/jbc.M704026200 . free .
7. Roughley PJ, White RJ, Cs-Szabo G, Mort JS . Changes with age in the structure of fibromodulin in human articular cartilage . Osteoarthritis and Cartilage . 4 . 3 . 153–61 . 1996 . 8895216 . 10.1016/s1063-4584(96)80011-2. free .
8. Smith MM, Melrose J . Proteoglycans in normal and healing skin . Adv Wound Care . 4 . 3 . 152–73 . 2015 . 25785238 . 10.1089/wound.2013.0464 . 4352701.
9. Juneja SC, Veillette C . Defects in tendon, ligament, and enthesis in response to genetic alterations in key proteoglycans and glycoproteins: a review . Arthritis . 2013 . 1–30 . 2013 . 24324885 . 10.1155/2013/154812 . 3842050. free .